Mechanisms by which LRP1 Protects the Vasculature

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DESCRIPTION (provided by applicant): Aortic aneurysms and aortic dissections account for 1% to 2% of all deaths in Western countries, and are usually asymptomatic until they rupture which most often results in death. Unfortunately, our current understanding of the molecular mechanisms leading to aneurysm formation is limited. Genome wide association studies reveal that the Lrp1 gene represents a susceptibility locus for abdominal aortic aneurysms. LRP1 encodes the LDL receptor related protein 1 (LRP1), a large endocytic and signaling receptor that regulates important physiological processes. Our recent studies reveal that mice in which the Lrp1 gene is selectively deleted in smooth muscle cells (smLRP1-/- mice) develop thoracic aneurysms. These mice display all of the symptoms detected in the human disease, including extensive in vivo aortic root and thoracic aortic dilatation, elastic lamina disorganization, recruitment of inflammatory cells into the vessel wall and excess collagen deposition. Proteomic studies revealed accumulation of proteases in the vessel wall, including HtrA1 (high-temperature requirement factor A1) and mast cell protease 4 (mMCP-4), the murine ortholog of human chymase. Both of these proteases are involved in matrix and elastic lamina degradation. Studies in Aim 1 will test the hypothesis that SMC LRP1 protects the vasculature by modulating protease activity, especially HtrA1 and mMCP-4, which in turn regulates the integrity of the elastic laminae. Ultrastructure studies of the aortic wall in smLRP1-/- mice reveal abnormal SMC. The TGF signaling pathway is a major pathway that is responsible for maintaining SMC in a contractile phenotype, and our preliminary data reveal that LRP1 binds several TGF family members and is required for the non-canonical signaling mediated by TGF Experiments in Aim 2 will test the hypothesis that LRP1 modulates SMC phenotypic transitions by regulating the TGF signaling pathway. Finally, we have initiated studies in collaboration with Dianna Milewicz (UT Houston) who has performed exome and Sanger sequencing of DNA from families with thoracic aortic aneurysms and acute aortic dissections. These studies identified several extremely rare LRP1 variants that segregate with aortic disease in these families, providing strong evidence that they are associated with the disease. Analysis of the amino acid substitutions in several of these variants suggest a strong rational for altered ligand binding and altered function in LRP1. Studies in Aim 3 will test the hypothesis that these rare variants result in defective LRP1 function, which in turn contributes to the development of this disease.